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Pulla V.K.,Birla Institute of Technology and Science | Sriram D.S.,Birla Institute of Technology and Science | Sriram D.S.,Incozen Therapeutics Private Ltd | Viswanadha S.,Incozen Therapeutics Private Ltd | And 4 more authors.
Journal of Chemical Information and Modeling | Year: 2016

Silent mating-type information regulation 2 homologue 1 (SIRT1), being the homologous enzyme of silent information regulator-2 gene in yeast, has multifaceted functions. It deacetylates a wide range of histone and nonhistone proteins; hence, it has good therapeutic importance. SIRT1 was believed to be overexpressed in many cancers (prostate, colon) and inflammatory disorders (rheumatoid arthritis). Hence, designing inhibitors against SIRT1 could be considered valuable. Both structure-based and ligand-based drug design strategies were employed to design novel inhibitors utilizing high-throughput virtual screening of chemical databases. An energy-based pharmacophore was generated using the crystal structure of SIRT1 bound with a small molecule inhibitor and compared with a ligand-based pharmacophore model that showed four similar features. A three-dimensional quantitative structure-activity relationship (3D-QSAR) model was developed and validated to be employed in the virtual screening protocol. Among the designed compounds, Lead 17 emerged as a promising SIRT1 inhibitor with IC50 of 4.34 μM and, at nanomolar concentration (360 nM), attenuated the proliferation of prostate cancer cells (LnCAP). In addition, Lead 17 significantly reduced production of reactive oxygen species, thereby reducing pro inflammatory cytokines such as IL6 and TNF-α. Furthermore, the anti-inflammatory potential of the compound was ascertained using an animal paw inflammation model induced by carrageenan. Thus, the identified SIRT1 inhibitors could be considered as potent leads to treat both cancer and inflammation. © 2015 American Chemical Society. Source


Pulla V.K.,Birla Institute of Technology and Science | Sriram D.S.,Birla Institute of Technology and Science | Sriram D.S.,Incozen Therapeutics Private Ltd | Soni V.,Birla Institute of Technology and Science | And 3 more authors.
Chemical Biology and Drug Design | Year: 2015

Nicotinamide phosphoribosyltransferase (NAMPT) is a rate limiting enzyme that plays an important role in the synthesis of nicotinamide adenine dinucleotide (NAD) via a salvage pathway. Along with a role in bioenergetics, NAMPT regulates the activity of proteins such as SIRT-1 that utilize NAD as a cofactor. As NAD metabolism is usually high in diseased conditions, it has been hypothesized and proven that NAMPT is over expressed in various cancers and inflammatory disorders. Inhibitors targeting NAMPT could therefore be useful in treating disorders arising from aberrant NAMPT signalling. In this study, inhibitors against NAMPT were designed using an energy-based pharmacophore strategy and evaluated for efficacy in cellular assays. Besides reducing cellular pools of NAD and NMN, NAMPT inhibitors decreased concentrations of reactive oxygen species as well as mRNA levels of TNFα and IL6, thereby implicating their potential in alleviating the inflammatory process. In addition, reduced NAD levels corroborated with an induction of apoptosis in prostate cancer cell lines. © 2015 John Wiley & Sons A/S. Source


Veeraraghavan S.,Incozen Therapeutics Private Ltd | Veeraraghavan S.,University | Thappali S.,Incozen Therapeutics Private Ltd | Viswanadha S.,Incozen Therapeutics Private Ltd | And 4 more authors.
Journal of Pharmaceutical and Biomedical Analysis | Year: 2014

Efficacy assessments using a combination of ruxolitinib and nilotinib necessitate the development of a high precision analytical method for determination of both drugs in plasma. A high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the simultaneous determination of ruxolitinib and nilotinib in rat plasma. Extraction of ruxolitinib, nilotinib and dasatinib (internal standard; IS) from 50. μl rat plasma was carried out by protein precipitation with methanol. Chromatographic separation of analytes was performed on YMC pack ODS AM (150. mm. ×. 4.6. mm, 5. μm) column under gradient conditions with acetonitrile:2.0. mM ammonium acetate buffer as the mobile phase at a flow rate of 1. ml/min. Precursor ion and product ion transition for both analytes and IS were monitored on a triple quadrupole mass spectrometer, operated in the selective reaction monitoring with positive ionization mode. Method was validated over a concentration range of 0.16-247. ng/ml for ruxolitinib and 0.86-219. ng/ml for nilotinib. Mean extraction recovery for ruxolitinib, nilotinib, and IS of 99.6%, 97.6% and 90.3% were consistent across low, medium, and high QC levels. Precision and accuracy at low, medium and high quality control levels were less than 15% across analytes. Bench top, wet, freeze-thaw and long term stability were evaluated for both analytes. The analytical method was applied to support a pharmacokinetic study of simultaneous estimation of ruxolitinib and nilotinib in Wistar rat. Assay reproducibility was demonstrated by re-analysis of 18 incurred samples. © 2014 Elsevier B.V. Source


Veeraraghavan S.,Incozen Therapeutics Private Ltd | Veeraraghavan S.,University | Viswanadha S.,Incozen Therapeutics Private Ltd | Thappali S.,Incozen Therapeutics Private Ltd | And 2 more authors.
Journal of Pharmaceutical and Biomedical Analysis | Year: 2015

Efficacy assessments using a combination of ibrutinib and lenalidomide necessitate the development of an analytical method for determination of both drugs in plasma with precision. A high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the simultaneous determination of lenalidomide, ibrutinib, and its active metabolite PCI45227 in rat plasma. Extraction of lenalidomide, ibrutinib, PCI45227 and tolbutamide (internal standard; IS) from 50. μl rat plasma was carried out by liquid-liquid extraction with ethyl acetate:dichloromethane (90:10) ratio. Chromatographic separation of analytes was performed on YMC pack ODS AM (150. mm. ×. 4.6. mm, 5. μm) column under gradient conditions with acetonitrile:0.1% formic acid buffer as the mobile phases at a flow rate of 1. ml/min. Precursor ion and product ion transition for analytes and IS were monitored on a triple quadrupole mass spectrometer, operated in the selective reaction monitoring with positive ionization mode. Method was validated over a concentration range of 0.72-183.20. ng/ml for ibrutinib, 0.76-194.33. ng/ml for PCI-45227 and 1.87-479.16. ng/ml for lenalidomide. Mean extraction recovery for ibrutinib, PCI-45227, lenalidomide and IS of 75.2%, 84.5%, 97.3% and 92.3% were consistent across low, medium, and high QC levels. Precision and accuracy at low, medium and high quality control levels were less than 15% across analytes. Bench top, wet, freeze-thaw and long term stability was evaluated for all the analytes. The analytical method was applied to support a pharmacokinetic study of simultaneous estimation of lenalidomide, ibrutinib, and its active metabolite PCI-45227 in Wistar rat. Assay reproducibility was demonstrated by re-analysis of 18 incurred samples. © 2014 Elsevier B.V. Source


Patel P.N.,National Institute of Pharmaceutical Education and Research | Samanthula G.,National Institute of Pharmaceutical Education and Research | Sridhar V.,Incozen Therapeutics Private Ltd | Arla R.,Incozen Therapeutics Private Ltd | And 2 more authors.
Analytical Methods | Year: 2014

Dasatinib (DST), a tyrosine kinase inhibitor, is a novel anticancer agent and Sitagliptin (STG) is an antidiabetic agent of dipeptidyl peptidase-IV inhibitor class. A novel, sensitive and specific liquid chromatography tandem mass spectrometry (LC-MS/MS) based method has been developed for simultaneous monitoring of plasma levels of STG and DST in rat plasma. Both analytes and an internal standard (tolbutamide) were chromatographed on YMC-Pack ODS-AM (50 mm × 4.6 mm i.d., 3 μm) using a methanol:2 mM ammonium acetate binary gradient mobile phase at a flow rate of 1 ml min-1 with a splitter (1:1) over a 5 min run time. Detection of analytes was performed on a LC-MS/MS system in multiple reaction monitoring (MRM) mode. The transitions monitored were 488.1 → 401.0, 408.1 → 174.0 and 271.1 → 155.0 for DST, STG and IS, respectively. The method was validated over a concentration range of 5.41-1029.60 ng ml-1 for DST and 5.64-1073.56 ng ml-1 for STG. The lower limit of quantification was 5.41 ng ml-1 and 5.64 ng ml-1 for DST and STG, respectively. Recoveries from spiked controls were >82% for the analytes and the internal standard at all QC levels. The intra- and inter-batch precision and accuracy across four quality control levels met established criteria of US Food and Drug Administration guidelines. This method was successfully applied to monitor the pharmacokinetic profile of both STG and DST in Wistar rats. This method can be applicable for pharmacokinetic drug-drug interaction studies. This journal is © 2014 The Royal Society of Chemistry. Source

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